# NM_033337.3(CAV3):c.165del (p.Asp55fs)

https://sugi.bio/variant/cav3-p-asp55fs

## Summary

**CAV3 p.Asp55fs (c.165del)** is classified **Uncertain significance** in CAV3 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2023-03-10). Very rare (popmax 0.00133%, afr); Associated with Cardiovascular phenotype.

**At a glance:** Uncertain significance · review: Multiple submitters · rsID rs780411707 · 2 submitters · 2 linked conditions · very rare (popmax 0.00133%, afr)

## For patients & families {#patients}

This is a change in the CAV3 gene that is currently of uncertain significance — a definitive interpretation has not yet been established, submitted by 2 submitters, and is linked to Cardiovascular phenotype.

*Reference information, not medical advice, and not a prediction for any individual. A genetic counselor or clinician can interpret what it means for you and your family.*

**Support & next steps:** [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [CAV3](https://sugi.bio/atlas/gene/CAV3/) |
| Protein change (HGVS p.) | p.Asp55fs |
| Coding change (HGVS c.) | c.165del |
| MANE Select transcript | [NM_033337](https://www.ncbi.nlm.nih.gov/nuccore/NM_033337) |
| dbSNP | [rs780411707](https://www.ncbi.nlm.nih.gov/snp/rs780411707/) |
| Variant type | Deletion |
| Location | chr3:8745576-8745576 (GRCh38) |
| ClinVar | [VCV639987](https://www.ncbi.nlm.nih.gov/clinvar/variation/639987/) |

**All HGVS expressions:** `LRG_329:g.16767del`, `LRG_329t1:c.165del`, `NC_000003.11:g.8787262del`, `NC_000003.12:g.8745576del`, `NG_008797.2:g.16767del`, `NM_001234.5:c.165del`, `NM_033337.2:c.165delC`, `NM_033337.3:c.165del`

## Computational & population evidence {#evidence}

**Concordance:** Mixed / partial computational evidence (see below).

- **Missense predictors (AlphaMissense/REVEL/SaProt) do not apply** to this variant type — they score amino-acid substitutions only. For non-missense variants the computational signal comes from conservation (below), not from a missing predictor score.
- Conservation: phyloP 11.125, GERP 2.68, phastCons 1 — highly conserved position (PP3-type support)
- Molecular consequence: **frameshift** — a predicted loss-of-function variant. Gene population constraint: LOEUF 1.064, pLI 0.039666. *Descriptive; not an applied PVS1 code.*
- Nonsense-mediated decay: the premature termination codon is **in the last exon (2 of 2)** — predicted to **escape NMD**, so the truncated protein is likely expressed. An input to PVS1, not an applied code.
- CADD: **PHRED 18.93**. No single ClinGen-calibrated threshold exists and the expert panels that use CADD disagree — GUCY2D/AIPL1 require ≥ 20.0 for an untranslated-region variant, ABCA4 ≥ 28.1 for a synonymous or indel variant, the Pulmonary Hypertension panel imports Pejaver 2022's missense-calibrated numbers, and the Antibody Deficiencies panel declines CADD entirely for PIK3CD. CADD v1.7 also incorporates Zoonomia phyloP, so it partly re-expresses the conservation above. *Descriptive; no threshold applied.*
- SpliceAI: **not assessed** — the release is built from a substitutions-only source, so it holds no deletion variants. That is a property of the dataset, not of the variant, and is not evidence against a splicing effect.
- Population frequency (gnomAD v4.1): grpmax **0.00133%** (afr) · 1/74,918 in the highest group · 1/152,136 alleles overall — very rare (popmax 0.00133%, afr).

*Computational predictors are not independent (ClinGen Variant Classification guidance): AlphaMissense (Cheng et al. 2023) carries the ACMG weight for missense and conservation (phyloP/GERP/phastCons) for non-missense; REVEL (Pejaver-2022 calibrated strength bands) and SaProt (Su et al. 2023, structure-aware, ClinVar-independent protein language model, raw LLR) are shown as orthogonal agreement signals, not additive. For frequency, the gnomAD v4.1 grpmax filtering allele frequency (FAF95) is ClinGen's designated BA1/BS1 input (gnomAD v4 guidance v3.0, June 2025); BA1/BS1 thresholds are disease-specific, not a blanket 5%. Predictions, not a clinical determination.*

## Gene constraint & dosage {#gene-context}

**CAV3** population constraint: LOEUF 1.064, pLI 0.039666, missense-Z 0.99211. *Lower LOEUF and higher pLI indicate a gene that tolerates loss-of-function poorly; ClinGen dosage is the curated haploinsufficiency call.*

Curated gene–disease validity (ClinGen):

- **long QT syndrome** — Limited (AD)
- **caveolinopathy** — Definitive (AD)

## Protein context {#protein}


AlphaFold model confidence (whole protein): pLDDT 88.54, 55% of residues very-high.

## What this gene does {#gene-function}

*Describes the biological roles of CAV3 (the gene this variant disrupts) — not effects measured for this specific variant. A damaging variant is expected to affect these functions and pathways; the degree depends on the variant.*

**How this variant is thought to act:** CAV3's established molecular role includes calcium channel regulator activity.


### Pathways affected {#pathways}

CAV3 participates in **1 Reactome pathway** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [Smooth Muscle Contraction](https://reactome.org/content/detail/R-HSA-445355) | electronic |

### Molecular function & processes (GO — experimentally supported) {#go}

**Molecular function:** calcium channel regulator activity, sodium channel regulator activity, transmembrane transporter binding, protein-containing complex binding, molecular adaptor activity, connexin binding.

**Biological process:** regulation of heart rate, regulation of heart contraction, negative regulation of cardiac muscle hypertrophy, regulation of skeletal muscle contraction, regulation of signal transduction by receptor internalization, regulation of membrane potential.

## Clinical significance {#significance}

**Uncertain significance** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2023-03-10.

**Submitter consensus:** unanimous (2/2 Uncertain significance).

**Submission history:** 2 submissions (2022–2023); classifications have been stable.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Labcorp Genetics (formerly Invitae), Labcorp | Uncertain significance | criteria provided, single submitter | clinical testing | 2022-07-25 |
| Ambry Genetics | Uncertain significance | criteria provided, single submitter | clinical testing | 2023-03-10 |

## Associated conditions {#conditions}

[Cardiovascular phenotype](https://sugi.bio/atlas/disease/cardiovascular-phenotype/), [long QT syndrome](https://sugi.bio/atlas/disease/long-qt-syndrome/).

**Reported phenotype names (ClinVar):** Cardiovascular phenotype, Long QT syndrome.

## Similar variants {#similar}

Related CAV3 variant pages (same residue, condition, or type): [CAV3 p.Asp55Glu](/variant/cav3-p-asp55glu), [CAV3 p.Asp55Asn](/variant/cav3-p-asp55asn), [CAV3 p.Asp55Gly](/variant/cav3-p-asp55gly), [CAV3 p.Asp55=](/variant/cav3-p-asp55), [CAV3 p.Cys106fs](/variant/cav3-p-cys106fs), [CAV3 p.Ter152LysextTer?](/variant/cav3-p-ter152lysextter), [CAV3 p.Leu86fs](/variant/cav3-p-leu86fs), [CAV3 p.Glu4fs](/variant/cav3-p-glu4fs).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-11); gnomAD v4.1 (Broad Institute, built 2026-10-06); AlphaMissense (Cheng et al. 2023, © Google DeepMind — CC BY 4.0, built 2026-01-27); REVEL (Ioannidis et al. 2016 — ODbL, built 2026-07-13); SaProt (Su et al. 2023 — MIT, built 2026-07-14); SpliceAI (Illumina — free for non-commercial use, built 2026-10-13); CADD (Rentzsch et al. 2019, University of Washington — free for non-commercial use, built 2026-10-10); Conservation (phyloP/phastCons/GERP) (UCSC hg38 470-way mammal (Hiller Lab) + Ensembl Compara, built 2026-07-12); gnomAD Non-coding Constraint (Gnocchi) (Chen et al. 2024, Broad Institute — CC0, built 2026-10-11); gnomAD Regional Missense Constraint (Broad Institute — CC0, built 2026-10-13); Pangolin (Zeng & Li 2022 — CC BY 4.0, built 2026-10-11); Repeat regions (UCSC — RepeatMasker, TRF, segmental duplications, built 2026-10-11); ClinGen (ClinGen, built 2026-09-22); UniProt (CC BY 4.0); Reactome / GO (CC BY 4.0, built 2026-09-23); MaveDB (per-record license, built 2026-10-11); CIViC (CC0, built 2026-09-22); Orphanet (Orphanet, built 2026-06-12)

*Primary record: NCBI ClinVar (variation 639987). Classifications reflect these databases as of the page's build date and may change. Free reference use — not medical advice; consult the primary submitters and a clinician.*